In this completely revised Competiting Renewal Application, we will continue to pursue evidence that, during experimental sepsis after cecal ligation and puncture (CLP) in rodents, regulation of the inflammatory system is lost, resulting in a variety of harmful outcomes (organ dysfunction, loss of innate immune functions of phagocytic cells and activation of the clotting/fibrinolytic system). These outcomes are linked to uncontrolled activation of the complement system, generation of C5a and its interaction with its receptors (C5aR and C5L2). The balance in receptor engagement determines adverse and lethal outcomes. In Aim 1. we propose to use C5a receptor KO mice to determine how survival after CLP is affected and how systemic levels of inflammatory mediators are affected. In Aim 2 we will pursue our recent studies which indicate that in sepsis heart and cardiomyocyte (CM) dysfunction can be linked to interaction of C5a with C5aR on CMs, the signaling mechanisms involved, and the extent to which CMs can produce harmful mediators during sepsis. In Aim 3 we will pursue evidence that C5a can cause bleb formation and shedding of C5aR-enriched microparticles (MPs) in vitro and in vivo during sepsis and whether MP appearance after CLP is C5a dependent, the signaling mechanisms involved, and whether MPs represent a useful biomarker of sepsis. Finally, in Aim 4 we will pursue evidence that IL-17 production is driven by IL-23 and functions as "master switch" during sepsis to promote systemic production of harmful inflammatory mediators. The unifying theme in these studies is sepsis-induced production of C5a which, interacting with its receptors, results in highly destructive outcomes.